Pilot trial of EZN-2968, an antisense oligonucleotide inhibitor of hypoxia-inducible factor-1 alpha (HIF-1α), in patients with refractory solid tumors

Cancer Chemotherapy and Pharmacology

Volumn 73, Issue 2, 2014, Pages 343-348

  Jeong, Woondong ^a   Rapisarda, Annamaria ^b   Park, Sook Ryun ^a   Kinders, Robert J ^b   Chen, Alice ^a   Melillo, Giovanni ^b   Turkbey, Baris ^a   Steinberg, Seth M ^a   Choyke, Peter ^a   Doroshow, James H ^a   Kummar, Shivaani ^a  

^a NATIONAL CANCER INSTITUTE   (United States)

^b FREDERICK NATIONAL LABORATORY FOR CANCER RESEARCH   (United States)

Author keywords

Antiangiogenesis; HIF mRNA; Pharmacodynamics driven trials; Synthetic locked nucleic acid (LNA) oligodeoxynucleotide

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; EZN 2968; HYPOXIA INDUCIBLE FACTOR 1ALPHA; MESSENGER RNA; UNCLASSIFIED DRUG;

ADULT; AGED; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALKALINE PHOSPHATASE BLOOD LEVEL; ANEMIA; ARTICLE; ASPARTATE AMINOTRANSFERASE BLOOD LEVEL; CLINICAL ARTICLE; CLINICAL TRIAL; CREATININE BLOOD LEVEL; DIARRHEA; DRUG DOSE REDUCTION; DRUG DOSE REGIMEN; DRUG EFFICACY; DRUG SAFETY; DRUG TARGETING; DRUG TOLERABILITY; DYNAMIC CONTRAST ENHANCED MAGNETIC RESONANCE IMAGING; FATIGUE; FEMALE; GENE EXPRESSION REGULATION; HUMAN; HUMAN TISSUE; HYPOPHOSPHATEMIA; INFUSION RELATED REACTION; LEUKOPENIA; LIVER TOXICITY; LYMPHOCYTOPENIA; MALE; MULTIPLE CYCLE TREATMENT; NEPHROTOXICITY; NEUROENDOCRINE TUMOR; NEUTROPENIA; NUCLEAR MAGNETIC RESONANCE IMAGING; PILOT STUDY; PRIORITY JOURNAL; PROTEIN EXPRESSION; SOLID TUMOR; TISSUE LEVEL; TREATMENT RESPONSE; TUMOR BIOPSY;

AGED; BIOPSY; CELL LINE, TUMOR; FEMALE; HUMANS; HYPOXIA-INDUCIBLE FACTOR 1; INFUSIONS, INTRAVENOUS; MALE; MIDDLE AGED; NEOPLASMS; OLIGONUCLEOTIDES; OLIGONUCLEOTIDES, ANTISENSE; PILOT PROJECTS; RNA, MESSENGER;

EID: 84896032490     PISSN: 03445704     EISSN: 14320843     Source Type: Journal    
DOI: 10.1007/s00280-013-2362-z     Document Type: Article

References (20)

1. Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3:721-732
2. Schindl M, Schoppmann SF, Samonigg H, Hausmaninger H, Kwasny W, Gnant M, Jakesz R, Kubista E, Birner P, Oberhuber G (2002) Overexpression of hypoxia-inducible factor 1α is associated with an unfavorable prognosis in lymph node-positive breast cancer. Clin Cancer Res 8:1831-1837 (Pubitemid 34633742)
3. Shibaji T, Nagao M, Ikeda N, Kanehiro H, Hisanaga M, Ko S et al (2003) Prognostic significance of HIF-1 alpha overexpression in human pancreatic cancer. Anticancer Res 23:4721-4727 (Pubitemid 38173890)
4. Swinson DEB, Jones JL, Cox G, Richardson D, Harris AL, O'Byrne KJ (2004) Hypoxia-inducible factor-1α in non small cell lung cancer: relation to growth factor, protease and apoptosis pathways. Int J Cancer 111:43-50 (Pubitemid 38859281)
5. Hu Y, Liu J, Huang H (2013) Recent agents targeting HIF-1 alpha for cancer therapy. J Cell Biochem 114:498-509
6. Melillo G (2007) Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev 26:341-352
7. Aboul-Fadl T (2005) Antisense oligonucleotides: the state of the art. Curr Med Chem 12:2193-2214
8. Vester B, Wengel J (2004) LNA (locked nucleic acid): high-affinity targeting of complementary RNA and DNA. Biochemistry 43:13233-13241 (Pubitemid 39391124)
9. Raunak, Ravindra Babu B, Sorensen MD, Parmar VS, Harrit NH, Wengel J (2004) Oligodeoxynucleotides containing alpha-L-ribo configured LNA-type C-aryl nucleotides. Org Biomol Chem 2:80-89
10. Nimesh S, Gupta N, Chandra R (2011) Cationic polymer based nanocarriers for delivery of therapeutic nucleic acids. J Biomed Nanotechnol 7:504-520
11. Greenberger LM, Horak ID, Filpula D, Sapra P, Westergaard M, Frydenlund HF, Albaek C, Schroder H, Orum H (2008) A RNA antagonist of hypoxia-inducible factor-1 alpha, EZN-2968, inhibits tumor cell growth. Mol Cancer Ther 7:3598-3608
12. Patnaik A, Chiorean EG, Tolcher A, Papadopoulos K, Beeram M, Kee D, Waddell M, Gilles E, Buchbinder A (2009) EZN-2968, a novel hypoxia-inducible factor-1 (HIF-1) messenger ribonucleic acid (mRNA) antagonist: results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies. J Clin Oncol 27:2564
13. Cohen RB, Olszanski A, Figueroa J, Hurwitz H, Lokiec FM, Rezaï K, Berkowitz N, Buchbinder A (2011) Down-modulation of messenger ribonucleic acid (mRNA) by EZN-2968, an hypoxia-inducible factor-1(HIF-1α) mRNA antagonist, administered in adult patients with advanced solid tumors [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research, Orlando, Florida. AACR, Philadelphia (PA), abstract nr LB-407, 2-6 April 2011
14. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228-247
15. Park SR, Kinders RJ, Khin S, Hollingshead M, Parchment RE, Tomaszewski JE, Doroshow JH (2012) Validation and fitness testing of a quantitative immunoassay for HIF-1 alpha in biopsy specimens [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research, Chicago, Illinois. AACR, Philadelphia (PA), abstract nr 3616, 31 March-4 April 2012
16. Levin AA (1999) A review of the issues in the pharmacokinetics and toxicology of phosphorothioate antisense oligonucleotides. Biochim Biophys Acta 1489:69-84
17. Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW (1999) Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 59:5830-5835
18. Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157:411-421 (Pubitemid 30626905)
19. Keith B, Johnson RS, Simon MC (2012) HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer 12:9-22
20. Jeong W, Doroshow JH, Kummar S (2013) United States Food and Drug Administration approved oral kinase inhibitors for the treatment of malignancies. Curr Probl Cancer 37:110-144